Polystyrene NPs reshape PFOA-driven mitochondrial redox balance, pentose phosphate-nucleotide metabolism, and membrane lipid remodeling in Cipangopaludina cathayensis

Perfluorooctanoic acid (PFOA) and nanoplastics (NPs) frequently co-occur in freshwater systems, yet their interactive effects on mitochondria-centered toxicity in benthic mollusks remain poorly resolved. We conducted a 28-day exposure of the freshwater snail Cipangopaludina cathayensis at environmentally relevant concentrations, integrating redox biomarkers, mitochondrial functional phenotypes, TUNEL staining, and the IBRv2 index, together with hepatopancreas transcriptomics and mitochondrial metabolomics. PFOA was the dominant driver, eliciting a time-resolved profile of redox imbalance and mitochondrial bioenergetic dysfunction, characterized by suppressed antioxidant capacity, aggravated oxidative damage, reduced membrane potential, ATP depletion, impaired respiratory-chain activities, ultrastructural disruption, and increased TUNEL-positive signals. NPs alone mainly induced mild perturbations or stress-adaptive responses. Notably, at the tested environmentally relevant concentrations co-exposure did not exacerbate injury beyond PFOA alone; instead, it reshaped the response architecture by reconfiguring mitochondrial redox balance, pentose phosphate-nucleotide metabolism, and membrane lipid remodeling, with prominent lipid peroxidation and membrane-lipid turnover signatures. Multi-omics integration further indicated coordinated shifts in pentose phosphate-nucleotide metabolism and glutathione-related processes alongside altered mitochondrial redox balance, consistent with enhanced membrane lipid remodeling and downstream mitochondrial failure. Overall, this study identifies mitochondria-centered response pathways associated with PFOA-NPs co-exposure in freshwater mollusks and provides a scientific basis for ecological risk assessment and pollution management.